Neurocognitive follow-up in adult siblings with Phelan-McDermid syndrome due to a novel SHANK3 splicing site mutation.

Minna Kankuri‐Tammilehto,Oili Sauna‐Aho,Maria Arvio

doi:10.1002/mgg3.1780

Abstract

BackgroundPhelan–McDermid syndrome (PMD) is usually not only caused by 22q13.3 deletion but also pathogenic variants (mutations) of SHANK3 gene. PMD is characterized by global intellectual disability, severely delayed or absent speech, and features of autism spectrum disorder and susceptibility to psychotic behavior. Here, we describe a neurocognitive follow‐up and genetic etiology for two siblings with PMD.MethodComparative genomic hybridization (CGH) array test was normal and no 22q13.3 deletion was observed. For this reason, whole exome sequencing (WES) analyzed the siblings’ and the parents’ DNA sample.ResultsThe results of the siblings strongly suggest that the SHANK3 gene variant c.2313+1G>A is pathogenic and PMD can be inherited from a mosaic father for this gene variant. Both siblings learned new skills until puberty but experienced a neuropsychiatric disaster after the age of 14 years experienced neurocognitive decline and it was sharp for one of the siblings.ConclusionThe long‐term observations are sparse in PMD and SHANK3 mutations. This is the neurocognitive follow‐up from childhood to middle ages, where a sharp neurocognitive decline was observed. We conclude that progressive neuropsychiatric symptoms in adolescence are a universal clinical clue for PMD diagnosis and an underlying SHANK3 splicing site mutation.

Highlights

People with an intellectual disability (ID) form a most heterogenic group of people regarding etiology, severity, and associated impairments of ID
We report two siblings with Phelan–McDermid syndrome (PMD) due to a previously not a well-known splice site variant in SHANK3 gene and a more than 25 years neurocognitive follow-up
At the age of 14, he managed to concentrate on the required tasks. His verbal reasoning was stronger than non-verbal, and his verbal skills corresponded the level of moderate ID, whereas nonverbal skills corresponded severe ID according to WPPSI-R (Wechsler, 1989) and Nepsy (Korkman, 1988, 1997)

Summary

| INTRODUCTION

People with an intellectual disability (ID) form a most heterogenic group of people regarding etiology, severity, and associated impairments of ID. At the age of 8, he was described as restless and having poor concentration skills and results of psychological assessment according to WPPSI-R (Wechsler, 1989), Nepsy (Korkman, 1988, 1997), and ITPA (Stewart, 1977) indicated moderate ID. At the age of 14, he managed to concentrate on the required tasks His verbal reasoning was stronger than non-verbal, and his verbal skills corresponded the level of moderate ID, whereas nonverbal skills corresponded severe ID according to WPPSI-R (Wechsler, 1989) and Nepsy (Korkman, 1988, 1997). Five years later it was estimated that the patient had benefited from the diet and was less anxious than before the diet Still, he kept on moving all the wake time, clapped and rubbed hands, slept on average 4 hours a day, did not speak, needed constant guidance but was able to bike together with an accompanying person in rural streets. Whole exome sequencing (WES) analyzed the sisters’ and the parents’ DNA sample

| Result of genetic studies

Findings

| DISCUSSION